Functional Polymorphisms in the p53 Pathway Genes on the Genetic Susceptibility to Zika Virus Teratogenesis.
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ABSTRACT:
SUBMITTER: Gomes JA
PROVIDER: S-EPMC8294037 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGenetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual's susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development.MethodsWe genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case-control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform.ResultsIn the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12-2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers.ConclusionsThese results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas.
| S-EPMC3655843 | biostudies-literature
Project description:BackgroundDue to the diversity of studies in animal models reporting that molecular mechanisms are involved in the teratogenic effect of the Zika virus (ZIKV), the objective of the present study is to evaluate the methodological quality of these studies, as well as to demonstrate which genes and which molecular pathways are affected by ZIKV in different animal models.MethodsThis search will be performed in four databases: PubMed/MEDLINE, EMBASE, Web of Science, and Scopus, as well as in the grey literature. The studies selection process will be reported through the PRISMA Statement diagram model. All studies describing the molecular mechanisms possibly involved in the development of malformations caused by embryonic/fetal ZIKV exposure in animal models with an appropriate control group and methodology will be included (including, for instance, randomized and non-randomized studies). All animals used as experimental models for ZIKV teratogenesis may be included as long as exposure to the virus occurred during the embryonic/fetal period. From the selected studies, data will be extracted using a previously prepared standard form. Bias risk evaluation will be conducted following the SYRCLE's Risk of Bias tool. All data obtained will be tabulated and organized by outcomes (morphological and molecular).DiscussionWith the proposed systematic review, we expect to present results about the methodological quality of the published studies with animal models that investigated the molecular mechanisms involved in the teratogenic effect of ZIKV, as well as to show the studies with greater reliability.Systematic review registrationPROSPERO CRD42019157316.
| S-EPMC8164069 | biostudies-literature
Project description:Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p < 0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant effect prediction tools showed 97% of the variants with potential to influence in these genes regulation. DGE analysis showed a significant reduction of ESCO2 in hPSCs after thalidomide exposure.
| S-EPMC6684595 | biostudies-literature
Project description:The allele frequencies of two functional single-nucleotide polymorphisms (SNPs) in the p53 pathway, the MDM2 SNP309 and TP53 Arg72Pro, vary dramatically among populations. That the frequencies of the TP53 SNP follow a clinal distribution may suggest that selective pressure from environmental variables correlated with latitude contributed to these observed population differences. Recently, winter temperature and UV radiation were found to be significantly correlated with the TP53 and the MDM2 SNPs, respectively, in East Asians; whether these correlations are more extreme than expected based upon nonselective factors such as patterns of human migration remains unclear. Here, we genotyped these two SNPs in 971 unrelated individuals from 52 unique populations worldwide and tested for correlations with both latitude and a number of climate-related environmental variables on a global scale, controlling for these neutral processes. The TP53 SNP was associated with a significant selection signal for a few climate variables, such as short-wave radiation flux in the winter, but these signals were no longer significant after correction for multiple tests. The MDM2 SNP did not exhibit a significant signal with any climate variable. Therefore, these SNPs are unlikely to be under selective pressure driven by these variables. Thus, these data underscore the need to incorporate population history when assessing signatures of selection.
| S-EPMC3063984 | biostudies-literature
Project description:Polymorphisms in microRNA (miRNA) genes could influence the expression of miRNAs that regulate the PI3K/Akt signalling pathway and play crucial roles in cancer susceptibility. To investigate the association of single nucleotide polymorphisms (SNPs) in miRNA genes of PI3K/Akt with cervical intraepithelial neoplasia (CIN) and cervical cancer (CC), nine SNPs located in miRNA genes were selected for genotyping, and the association of these SNPs with CIN and CC risk was evaluated. A total of 1,402 participants were enrolled in the current study, including 698 healthy individuals in the control group, 431 patients with CC, and 273 patients with CIN. Nine SNPs in miRNA genes (rs107822 in miR-219a, rs10877887 in let-7i, rs2292832 in miR-149, rs353293 in miR-143, rs3746444 in miR-499, rs3803808 in miR-132, rs4078756 in miR-10b, rs629367 in let-7a, and rs7372209 in miR-26a) were genotyped using MassArray, and the association of these SNPs with CIN and CC were analysed. The results showed that the frequencies of rs107822 in miR-219a and rs2292832 in miR-149 were significantly different between the control and CC groups (p < 0.005). The C allele of rs107822 in miR-219a was associated with an increased risk of CC (OR = 1.29, 95%CI:1.09-1.54) whereas the C allele of rs2292832 in miR-149 was associated with a decreased risk of CC (OR = 0.77, 95%CI:0.64-0.92). The results of inheritance model analysis showed that the best-fit inheritance models for rs107822 and rs2292832 were log-additive. The 2CC + CT genotype of rs107822 could be a risk factor for CC when compared with the TT genotype (OR = 1.28, 95%CI:1.08-1.51). The 2CC + CT genotype of rs2292832 could be a protective factor against CC when compared with the TT genotype (OR = 0.76, 95%CI:0.64-0.92). However, no association of these SNPs with CIN was found in the current study. Our results suggest that rs107822 in the promoter region of miR-219a and rs2292832 in pre-miR-149 region are associated with the risk of CC.
| S-EPMC9047912 | biostudies-literature
Project description:Continuing advances in genotyping technologies and the inclusion of DNA collection in observational studies have resulted in an increasing number of genetic association studies.To evaluate the overall progress and contribution of candidate gene association studies to current understanding of the genetic susceptibility to cancer.We systematically examined the results of meta-analyses and pooled analyses for genetic polymorphisms and cancer risk published through March 2008.We identified 161 meta-analyses and pooled analyses, encompassing 18 cancer sites and 99 genes. Analyses had to meet the following criteria: include at least 500 cases, have cancer risk as outcome, not be focused on HLA antigen genetic markers, and be published in English.Information on cancer site, gene name, variant, point estimate and 95% confidence interval (CI), allelic frequency, number of studies and cases, tests of study heterogeneity, and publication bias were extracted by 1 investigator and reviewed by other investigators.These 161 analyses evaluated 344 gene-variant cancer associations and included on average 7.3 studies and 3551 cases (range, 508-19 729 cases) per investigated association. The summary odds ratio (OR) for 98 (28%) statistically significant associations (P value <.05) were further evaluated by estimating the false-positive report probability (FPRP) at a given prior probability and statistical power. At a prior probability level of 0.001 and statistical power to detect an OR of 1.5, 13 gene-variant cancer associations remained noteworthy (FPRP <0.2). Assuming a very low prior probability of 0.000001, similar to a probability assumed for a randomly selected single-nucleotide polymorphism in a genome-wide association study, and statistical power to detect an OR of 1.5, 4 associations were considered noteworthy as denoted by an FPRP value <0.2: GSTM1 null and bladder cancer (OR, 1.5; 95% CI, 1.3-1.6; P = 1.9 x 10(-14)), NAT2 slow acetylator and bladder cancer (OR, 1.46; 95% CI, 1.26-1.68; P = 2.5 x 10(-7)), MTHFR C677T and gastric cancer (OR, 1.52; 95% CI, 1.31-1.77; P = 4.9 x 10(-8)), and GSTM1 null and acute leukemia (OR, 1.20; 95% CI, 1.14-1.25; P = 8.6 x 10(-15)). When the OR used to determine statistical power was lowered to 1.2, 2 of the 4 noteworthy associations remained so: GSTM1 null with bladder cancer and acute leukemia.In this review of candidate gene association studies, nearly one-third of gene-variant cancer associations were statistically significant, with variants in genes encoding for metabolizing enzymes among the most consistent and highly significant associations.
| S-EPMC2772197 | biostudies-literature
Project description:BackgroundGlioblastoma is the most aggressive and common malignant primary brain tumor in adults. Many genetic, epigenetic and genomic mutations have been identified in this tumor, but no driving cause has been identified yet for glioblastoma pathogenesis. Autophagy has proved to be deregulated in different diseases such as cancer where it has a dual role, acting as a tumor suppression mechanism during the first steps of tumor development and promoting cancer cells survival in stablished tumors.MethodsHere, we aimed to assess the potential association between several candidate polymorphisms in autophagy genes (ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183, ATG5 rs2245214, NOD2 rs2066844 and rs2066845) and glioblastoma susceptibility.ResultsOur results showed a significant correlation between ATG2B rs3759601, ATG10 rs1864183 and NOD2 rs2066844 variants and higher risk to suffer glioblastoma. In addition, the relationship between the different clinical features listed in glioblastoma patients and candidate gene polymorphisms was also investigated, finding that ATG10 rs1864183 might be a promising prognosis factor for this tumor.ConclusionsThis is the first report evaluating the role of different variants in autophagy genes in modulating glioblastoma risk and our results emphasize the importance of autophagy in glioblastoma development.
| S-EPMC8818195 | biostudies-literature
Project description:The tumor suppressor protein p53 is a powerful regulator of the embryo's susceptibility to diverse teratogenic stimuli, functioning both as a teratogenesis inducer and suppressor. However, the targets that p53 engages to fulfill its functions remain largely undefined. We asked whether the microRNA (miRNA) miR-34 family, identified as one of the main targets of p53, mediates its function as a teratogenesis inducer. For this, pregnant ICR-, p53- and miR-34a-deficient mice, as well as rats, were exposed to 5-aza-2'-deoxycytidine (5-aza), a teratogen inducing limb reduction anomalies (LRA) of the hindlimbs in mice and either the hindlimbs or forelimbs in rats. Using hind- and forelimb buds of 5-aza-exposed embryos, we identified that the miR-34 family members are the most upregulated miRNAs in mouse and rat limb buds, with their increase level being significantly higher in limb buds destined for LRA. We showed that p53 mediates the 5-aza-induced miR-34 transcription followed by met proto-oncogene and growth-arrest-specific 1 target suppression in embryonic limb buds. We demonstrated that p53 regulates the teratogenic response to 5-aza acting as a teratogenesis inducer albeit miR-34a deletion does not affect the susceptibility of mice to 5-aza. Overall, our study thoroughly characterizes the expression and regulation of miR-34 family in teratogen-resistant and teratogen-sensitive embryonic structures and discusses the involvement of epigenetic miRNA-mediated pathway(s) in induced teratogenesis.
| S-EPMC6624319 | biostudies-literature
Project description:To investigate whether common variants in the oxidative pathway genes influence inflammatory bowel disease (IBD) risk among Moroccan patients.The distribution of (TAAA)n_rs12720460 and (CCTTT)n _rs3833912 NOS2A microsatellite repeats, HIF-1A_rs11549467 and NFKB1-94ins/delATTG_rs28362491 was analyzed in 507 subjects grouped in 199 IBD and 308 healthy controls. Genotyping was performed with polymerase chain reaction-fluorescent method and the TaqMan® allelic discrimination technology.The allele and genotype frequencies of HIF1A_ rs11549467, NFKB1_rs28362491 and NOS2A_ (TAAA)n did not differ significantly between patients and controls. Analysis of NOS2A_ (CCTTT)n markers evidenced differences between patients and healthy controls. A preferential presence of the (CCTTT)8 (P = 0.02; OR = 1.71, 95%CI: 1.07-2.74), (CCTTT)14 (P = 0.02; OR = 1.71, 95%CI: 1.06-2.76) alleles in IBD, (CCTTT)8 (P = 0.008; OR = 1.95, 95%CI: 1.17-3.23) in CD and (CCTTT)7 (P = 0.009; OR = 7.61, 95%CI: 1.25-46.08), (CCTTT)11 (P = 0.05; OR = 0.51, 95%CI: 0.25-1.01), (CCTTT)14 (P = 0.02; OR = 2.05, 95%CI: 1.07-3.94), (CCTTT)15 (P = 0.01; OR = 2.25, 95%CI: 1.16-4.35) repeats in UC patients indicated its possible association with higher disease risk which need to be confirmed in a larger sample size.Our results suggest that the NOS2A_ (CCTTT)n gene variations may influence IBD susceptibility in the Moroccan population.
| S-EPMC5743501 | biostudies-literature
Project description:ObjectiveObesity has been reaching epidemic levels in recent decades, with a growing body of research identifying predisposing genetic components. To explore the relationship of genetic factors contributing to obesity, an analytical computer-based gene-profiling approach utilizing an updated list of clinically relevant and known obesity-related genes was undertaken.MethodsAn updated list of 494 genes reportedly associated with obesity was compiled, and the GeneAnalytics profiling software was utilized to interrogate genomic databases from GeneCards® to cross-reference obesity gene sets against tissues and cells, diseases, genetic pathways, gene ontology (GO)-biological processes and GO-molecular functions, phenotypes, and compounds.ResultsObesity-related fields identified by GeneAnalytics algorithms included 8 diseases, 46 pathways, 62 biological processes, 22 molecular functions, 148 phenotypes, and 286 compounds impacting adipogenesis, signal transduction by G-protein coupled receptors, and lipid metabolism involving insulin-related genes (IGF1, INS, IRS1). GO-biological processes identified feeding behavior, cholesterol metabolic process, and glucose and cholesterol homeostasis pathways, while GO-molecular processes pertained to receptor binding, affecting glucose homeostasis, body weight, and circulating insulin and triglyceride levels.ConclusionsThe gene-profiling model suggests that pathogenesis of obesity relates to the coordination of biological responses to glucose and intracellular lipids possibly through a disruption of biochemical cascades and cellular signaling arising from affected receptors.
| S-EPMC5444946 | biostudies-literature